Authors: Gokul Thimmarayan, MD and Destiny F. Chau, MD - Arkansas Children’s Hospital /University of Arkansas for Medical Sciences, Little Rock, AR
An 18-month-old toddler with a history of Trisomy 21 is undergoing a full repair of a partial atrioventricular canal with cardiopulmonary bypass. Ten times the intended dose of tranexamic acid is administered during the procedure in error. In the early post-operative period, generalized tonic-clonic seizures are noted. Tranexamic acid induces seizures by the competitive antagonism of which of the following receptors?
Tranexamic acid (TXA) is an analog of lysine, which binds to plasminogen and prevents its conversion to plasmin, thereby inhibiting fibrinolysis and improving hemostasis. TXA use decreases the risk of bleeding after cardiac surgery with cardiopulmonary bypass in both the adult and pediatric populations. Epsilon aminocaproic acid (EACA), another lysine derivative, and aprotinin, a serine protease inhibitor, are other antifibrinolytic agents.
The reported dosing ranges and protocols for TXA differ greatly from a 10 to 100 mg/kg bolus prior to cardiopulmonary bypass (CPB) followed by an infusion at variable rates and/or an additional bolus in the pump prime. TXA use has been associated with an increased risk of thromboembolism, seizure, and renal dysfunction. Seizure frequency is correlated positively with higher doses of TXA (total TXA dose of >100 mg/kg), which was demonstrated in study of adult cardiac surgical patients by Kalavrouziotis et al. TXA-related seizures are most frequently reported in the early postoperative period after cardiac surgery and are associated with increased morbidity and mortality. In a propensity-score matched study of 3,739 pairs of pediatric patients undergoing cardiac surgery, Maeda et al. demonstrated an incidence of seizures of 1.6% in the patients treated with TXA versus 0.2% in those not treated with TXA.
A 2012 study by Lecker et al. used the mouse neuron as a model to investigate the mechanism of seizure due to TXA. The study demonstrated that TXA, which is a structural analog of the inhibitory neurotransmitter glycine, competitively binds to and inhibits the activity of glycine receptors. Thus, the authors postulated that blockade of inhibitory glycine receptors by TXA leads to neuronal hyperexcitability and lowers seizure threshold. The authors temporally measured the TXA concentration in serum and cerebrospinal fluid (CSF) in patients undergoing vascular surgery or cardiac surgery with cardiopulmonary bypass. The authors found that the peak TXA concentration in CSF occurs after the peak TXA concentration in serum. The peak concentration of TXA in CSF correlated with the reported observation that seizures occur more frequently in the early postoperative period. This time frame also coincides with the waning anti-convulsant effects of general anesthetic agents after surgery. The authors also postulated that enhancing glycine inhibitory potential could suppress seizures associated with TXA. Therefore, agents such as isoflurane, sevoflurane, and propofol, which are known to stimulate glycine receptor activity, could potentially be used to prevent or treat seizures induced by TXA.
EACA, which is also an analogue of lysine, is associated with a much lower incidence of seizures because it is a much weaker inhibitor at glycine receptors than TXA. In a study comparing the incidence of seizures in adult cardiac surgical patients treated with TXA or EACA, Martin et al. reported an incidence of 7.6% in the TXA group versus 3.3% in the EACA group.
Aspartate, and acetylcholine are excitatory neurotransmitters in the central nervous system. Thus far, they have not been associated with seizures caused by TXA.
The most effective way to prevent TXA-induced seizures is by utilizing doses at the lower end of the range known to be effective in reducing blood loss after surgery and by lowering the dose administered to patients with renal dysfunction, as it is primarily eliminated in the urine. Currently, there is not a clearly defined safe, yet effective dose of TXA.
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Lecker I, Wang DS, Romaschin AD, Peterson M, Mazer CD, Orser BA. Tranexamic acid concentrations associated with human seizures inhibit glycine receptors.J Clin Invest. 2012;122(12):4654-4666. doi:10.1172/JCI63375
Kalavrouziotis D, Voisine P, Mohammadi S, Dionne S, Dagenais F. High-dose tranexamic acid is an independent predictor of early seizure after cardiopulmonary bypass. Ann Thorac Surg . 2012;93(1):148-155. doi: 10.1016/j.athoracsur.2011.07.085
Lecker I, Wang D, Whissell P, Avramescu S, Mazer C, Orser B. Tranexamic acid-associated seizures: causes and treatment. Ann Neurol . 2016;79(1):18-26. Doi:10.1002/ama.24558
Martin K, Knorr J, Breur T et al. Seizures after open heart surgery: a comparison of E-aminocaproic acid versus tranexamic acid. J Cardiothorac Vasc Anesth. 2011;25:20-5. doi: 10.1053/j.jvca.2010.10.007.